The long-term objective of this proposal is to improve our understanding of neural control mechanisms in the pulmonary circulation. There are 4 specific aims designed to improve our knowledge of the regulation of the pulmonary vascular bed as it may relate to medical and surgical problems. The first aim is concerned with the nature of adrenergic receptors in the pulmonary vascular bed and the second specific aim is concerned with receptor subtypes stimulated by exogenous and nerve-released norepinephrine and the third specific aim is concerned with the comparison of receptor subtypes in the venous and upstream segments. The last specific aim is concerned with the influence of central nervous system stimulation on the pulmonary vascular bed. A new feature of this work is the hypothesis that pulmonary vascular responses to vasoactive substances are dependent on the existing level of vasoconstrictor tone in the pulmonary vascular bed. In the proposed studies, responses to alpha-1 and alpha-2 adrenoceptor agonists, catecholamines, sympathetic nerve and central nervous system stimulation will be investigated under baseline and high pulmonary vascular tone conditions. Right heart and transseptal catheterization techniques will be employed to maintain pulmonary blood flow and left atrial pressure constant. Pulmonary vascular tone will be raised to high steady levels by infusion of a stable prostaglandin analog, other vasoactive substances, and alveolar hypoxia. The proposed studies will improve our knowledge of control mechanisms in the pulmonary vascular bed and is significant from a clinical point of view. Preliminary studies have shown that responses to many vasoactive substances are tone-dependent, and it is known that pulmonary arterial pressure and vascular resistance are frequently elevated in patients in intensive care units. Adrenergic stimulants are frequently used in these patients with little understanding of how the actions of these drugs may be altered by increases in pulmonary vascular tone. The proposed studies will improve our understanding of how responses are changed by high levels of tone. The results obtained from these studies will provide new information which may be useful in the management of patients in the intensive care unit and may afford insight into new forms of therapy for the treatment of pulmonary hypertensive disorders.